It is only recently that the field became aware that certain tissue resident macrophages, including alveolar macrophages and microglial cells, are fetal stem cell derived lineages that behave markedly differently from blood monocyte derived macrophages. With such knowledge we need revisit the role of tissue resident macrophages as HIV-1 reservoirs and their contribution to viral persistence. We have shown that regulatory pathways in infected macrophages, such as pro-survival pathways, can be inhibited by targeting specific lncRNAs, thus driving selective cell death in infected but not uninfected macrophages. Such observations lay the groundwork for eradication of HIV-1 reservoirs, however, biologics, such as lncRNAs, are not as tractable as small molecule inhibitors to progress into therapeutics.

We have extensive, documented expertise in macrophage biology in both mouse and human lung, and we have maintained a productive anti-TB drug discovery program based on phenotypic screening for compounds active in infected macrophages. With this expertise we propose the identification and functional characterization of small molecule epigenetic inhibitors capable of modifying host macrophage programming to drive selective induction of cell death in specific myeloid cell lineages, and probing the underlying mechanism(s).